Local synaptic connections of basal forebrain neurons
Introduction
Comparative anatomical studies [14], [45] in the middle of the twentieth century emphasized the progressive development of the peculiar aggregated neurons in the basal forebrain (BF) in the mammalian phylogeny. Nonetheless, this region remained largely a terra incognita or ‘unnamed substance’ [50], [51] even in the ‘renaissance’ of neuroanatomy beginning in the late sixties. Recent interest in BF research was surged by discoveries in the late seventies and early eighties showing that a specific population of neurons in this region, namely those that use acetylcholine as their transmitter and project to the cerebral cortex, are seriously compromised in Alzheimer's disease (AD) [5], [24], [44], [81], [92], [93], [97]. Moreover, this neuronal damage could be, at least, partially responsible for the deteriorating cognitive functions in AD and related disorders [8], [12], [23], [79].
A combination of single unit recordings in the BF and EEG monitoring [16], [25], [26], [27], [28], [29], [30], [56], [72], [76] during various behaviors indicated that neocortical activation critically depends on basal forebrain inputs to the cortex. The neural circuitry underlying BF modulation of cortical activity still remained obscure, because these studies did not identify the recorded neurons chemically or morphologically [26]. Basal forebrain areas, including the medial septum/vertical limb of the diagonal band (MS/VDB), horizontal limb of the diagonal band (HDB), sublenticular substantia innominata and pallidal regions (ventral pallidum and globus pallidus) contain a heterogeneous population of neurons, where cholinergic, non-cholinergic projection neurons, and putative interneurons are intermingled along different ascending and descending pathways [111]. In vitro electrophysiological studies [3], [57], [73] as well as in vivo recordings of single neurons [77], in combination with transmitter identification of the recorded cells, opened the way to determine the specific function of the individual neural elements of the BF [32]. A precise knowledge of input–output relationships of specific neurons, including their local synaptic interactions will address many questions, such as how different neuronal populations of the BF may concurrently participate in generalized (e.g. arousal) or more selective functions, including cortical plasticity and attention (for discussion, see [111]). This review summarizes our preliminary studies1 concerning local axon collaterals of identified BF neurons and their possible postsynaptic targets.
Recent studies in rats suggest that cholinergic neurons make up only about half of the neurons projecting to neocortical areas, the rest contain various calcium-binding proteins [111], including parvalbumin, calretinin and calbindin. Fig. 1 shows the three-dimensional distribution of the two most prevalent basalocortical projection systems: the cholinergic and parvalbumin-containing neurons.
Section snippets
Cholinergic neurons
Studies using multiple retrograde tracers or antidromic activation of basalocortical neurons suggested that individual cholinergic axons are highly branched in their cortical terminal fields but seldom collateralize to innervate different parts of the cortex [6], [7], [64], [82]. Our own studies [Csordas and Zaborszky, in preparation] using multiple tracers delivered into functionally related cortical areas tend to support this notion, in contrast to some earlier [1], [70], and more recent
Globus pallidus
The cholinergic forebrain areas, including the globus pallidus, internal capsule and HDB contain numerous parvalbumin (PV)-positive neurons (Fig. 1). Most of the PV-positive neurons in pallidal areas are projection neurons, innervating the striatum [66], the thalamus and substantia nigra [83]. Fig. 3 shows a partially reconstructed PV neuron in the globus pallidus that discharged in a regular firing pattern with a mean firing rate of 40 Hz. This neuron was characterized by mildly varicose,
Other non-cholinergic projection neurons
Fig. 4 shows a retrogradely labeled, juxtacellularly filled neuron in the anterior amygdaloid area that projected to the prefrontal cortex. This neuron was tested for the presence for ChAT and for two calcium-binding proteins, PV and calretinin. None of these substances turned out to be localized within this neuron. A partial reconstruction of this neuron revealed that the dendrites were studded densely with spines and had a few initial axon collaterals with en passant varicosities.
Putative local circuit neurons
Fig. 5 shows a sparsely spiny neuron that was negative for ChAT and PV and is partially reconstructed. Around the cell body and occupying a large part of the dendritic arbor, a dense network of axon collaterals can be seen. These collaterals bear numerous large, bulbous varicosities. Within a space of about 0.14 mm3, 374 varicosities were counted. Within this axonal arborization volume, there are about 550 other neurons, including 300 calretinin, 200 cholinergic, 40 parvalbumin and 10
General discussion
Understanding of the cellular organization of the cerebral cortex, including the hippocampus, has advanced in the last twenty years primarily due to the application of intracellular electrophysiology with rigorous combination of correlated light and electron microscopic techniques [15], [36], [40], [48], [88]. Such methods, for technical reasons, were not adapted in their full capacity in the BF [67], [84], [86]. More recently, the application of the juxtacellular technique of Pinault [77], [80]
Acknowledgements
The research summarized in this paper was supported by NIH grant No. NS23945 (L.Z), S06 GM08223 and NSF-BIR-9413198 (A.D). We thank Dr J.M. Tepper for allowing us to use his equipment (NIH grant NS-34865). Special thanks are due to Dr Wei Lu, Derek Buhl and Elizabeth Rommer for their expert technical assistance.
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